N4-Acyl-5′-deoxy-5-fluorocytidine compounds have anti-tumor activity. See, for example, Japanese J. of Cancer Research, 1990, 81, 188-195, which is incorporated herein by reference in its entirety. One method of producing such a compound from 5′-deoxy-5-fluorocytidine is described in Japanese Patent Application Kokai No. 153,696/1989, which is incorporated herein by reference in its entirety. However, due to the length of the process, this process is not amenable for a large-scale commercial process.
One conventional commercial process for producing N4-acyl-5′-deoxy-5-fluorocytidine compounds involves synthesis of 5′-deoxy-5-fluoro-N4,2′,3′-triacylcytidine as an intermediate. See, for example, U.S. Pat. No. 5,453,497, issued Sep. 26, 1995, which is incorporated herein by reference in its entirety. This process requires a selective deacylation of hydroxy groups in the 2′- and 3′-positions to produce the final compounds. This method, along with an alternative process (see, for example, U.S. Pat. No. 5,476,932, issued Dec. 19, 1995, which is incorporated herein by reference in its entirety), is currently used to produce the anti-tumor agent in a commercial scale. However, these processes require the use of a large amount of carcinogenic halogenated solvent (e.g., methylene chloride), and tin (IV) chloride as a coupling catalyst.
Tin waste is not environmentally friendly and requires a special disposal procedure, thereby increasing the overall cost to the drug manufacture. Moreover, conventional commercial manufacturing processes for producing N4-acyl-5′-deoxy-5-fluorocytidine compounds require isolation of intermediate products, thereby further increasing the overall manufacturing time and cost.
Japanese Patent Nos. 60038395 and 60038396, which are incorporated herein by reference in their entirely, discuss an effort to improve the process for production of N4-acyl-5′-deoxy-5-fluorocytidine, via fluorination of cytidine and 5′-deoxycytidine in acetic acid/HF or trifluoroacetic acid solution. However, this method requires a large amount of Raney Ni (another heavy metal) for desulfurization to be environmentally feasible, and resulted in low yields of 5′-deoxycytidine.
Chem. Pharm. Bull. (Tokyo) 352 (1964), which is incorporated herein by reference in its entirety, discusses a method of acylating 5-fluorocytosine prior to the coupling step in an effort to provide a more efficient coupling process by using a less basic coupling partner for β-acetylfuranoside. Unfortunately, switching the sequence of coupling and acylation steps gave a higher amount of α-anomer formation, which is shown to be less stable than the β-anomer under the reaction conditions.
Besides the use of heavy metals in some conventional processes, there are other disadvantages in conventional commercial processes for producing N4-acyl-5′-deoxy-5-fluorocytidine compounds. For example, some conventional processes use a relatively large quantity of methylene chloride as a solvent in many of the reactions. Halogenated solvents, such as methylene chloride, require special disposal treatment, thus attributing to the increase in the overall drug production cost. Moreover, halogenated solvents pose a greater health risk to workers than most non-halogenated solvents.
Another disadvantage of conventional processes is that the overall yield of N4-acyl-5′-deoxy-5-fluorocytidine compounds is only about 62%. Any significant improvement in the overall yield will likely reduce the overall cost greatly for producing N4-acyl-5′-deoxy-5-fluorocytidine compounds.
Therefore, there is a need for a process for producing N4-acyl-5′-deoxy-5-fluorocytidine compounds that does not require the use of a heavy metal based catalyst. There is also a need for a process for producing N4-acyl-5′-deoxy-5-fluorocytidine compounds that uses a significantly less amount of halogenated solvents, such as methylene chloride. There is also a need to improve the overall production yield of N4-acyl-5′-deoxy-5-fluorocytidine compounds.